Site Mobile Navigation

Gene Therapy's Focus Shifts From Rare Illnesses

WHEN the gene responsible for Hunter's syndrome was discovered about 10 years ago, Joan Cohen was told by a doctor that it would take only five years to develop a gene therapy for the rare hereditary disease that afflicts her son.

Mrs. Cohen, who lives in Island Park, L.I., is still waiting. Even in its mild form, the disease often kills people by the time they reach 35. ''It's like a time bomb,'' Mrs. Cohen said. Her 17-year-old son, Adam, is just 4 feet 11 inches tall and suffers from leaky and enlarged heart valves, respiratory problems and deteriorated hearing. ''I'm sitting here with a kid that I know is going to die and there's nothing I can do that will stop it.''

When it first made headlines about a decade ago, gene therapy seemed the answer to the prayers of thousands of people affected by hereditary diseases. The idea is simple and eloquent. Many inherited diseases are caused by a faulty gene, which makes the body unable to produce some essential protein or enzyme. Gene therapy would deliver the needed gene to a person's cells, which would then begin producing the essential substance.

But gene therapy so far has not worked, mainly because it has been difficult to get the genes to the desired cells efficiently and have them produce enough of the needed protein. Scientific evidence of consistent improvement in patients is lacking so far, although some patients have reported gains.

The focus of gene therapy has shifted from inherited diseases toward more common ailments like cancer, AIDS and heart disease -- all areas that could prove more profitable. Many genetic disorders, and there are thousands of them, affect anywhere from a handful to a few thousand people worldwide, hardly a commercially promising prospect for pharmaceutical companies.

''The whole concept of gene therapy for genetic diseases doesn't fit the business model,'' said Dr. James M. Wilson, director of the institute for human gene therapy at the University of Pennsylvania and president of the American Society for Gene Therapy.

The situation raises the prospect that the Human Genome Project will discover an abundance of genes responsible for illnesses, but that no one will actually use those genes to help patients.

''It's only genes for things like obesity and baldness that are spurring further investigation,'' said Abbey S. Meyers, president of the National Organization for Rare Disorders.

Of the 244 gene therapy trials registered since 1989 with the Recombinant DNA Advisory Committee at the National Institutes of Health, about 150 are for cancer and another 23 are for H.I.V. Only 33 are for diseases caused by a defect in a single gene, and 16 of those are for cystic fibrosis, the most common inherited disease among Caucasians. Seventeen tests cover 12 other genetic diseases. Among trials registered since the beginning of 1997 the balance is even more lopsided -- 53 for cancer and 8 for hereditary diseases.

Although cancer has a genetic basis, it is a complex disease and many experts think gene therapy, at best, will become part of an arsenal of weapons achieving partial results. By contrast, diseases caused by a single defective gene could, at least in theory, be cured by gene therapy.

''It's the rare genetic diseases that give you neat model systems that are most likely to show success,'' said Dr. W. French Anderson, director of the gene therapy laboratories at the University of Southern California. ''So it's really ironic that we can't get the funding to do it.''

When he worked at N.I.H., Dr. Anderson participated in the first human gene therapy experiments, performed on two girls with a rare inherited immune deficiency. But now, he said, his gene therapy work is directed at cancer, cardiovascular disease and arthritis because that is where the funding is.

Because the technology so far has not worked on a large scale, the paucity of clinical trials aimed at inherited diseases has not been a major issue.

''Without the breakthroughs in technology, all the clinical trials wouldn't mean much in the end because they are not going to be successful,'' said Dr. Savio Woo, director of the institute for gene therapy and molecular medicine at Mount Sinai Medical Center in New York.

Some experts, as well as families with rare genetic diseases, are confident that once the technology works, money will become available. The Orphan Drug Act, which gives drug companies financial incentives to develop treatments for rare disorders, probably would cover gene therapy.

Still, some scientists say that recent improvements in technology promise to bring the business issue to the fore in a few years, and efforts to address it are starting.

The Food and Drug Administration and the National Institutes of Health have begun exploring whether clinical trials of gene therapy for rare genetic diseases could be compressed to make them less expensive and require fewer patients. One proposal would combine the first phase of trials, used to test for safety, and later stages that test for efficacy, said Dr. Stephen C. Groft, who heads the institutes' rare disease office.

Meanwhile, the University of Pennsylvania, the University of Southern California and the National Organization for Rare Disorders are discussing a joint effort to raise millions of dollars for gene therapy clinical trials on rare diseases.

Many patient groups are raising money to finance research, including gene therapy trials. The Fanconi Anemia Research Foundation, for example, has distributed $2.7 million since 1990 for research on that disease, in which the bone marrow fails to work. But many patient organizations are small and have been unable to raise such large sums.

An error has occurred. Please try again later.

You are already subscribed to this email.

Some say the Government will have to finance clinical trials for rare diseases. But the N.I.H., following a 1995 review of gene therapy, believes that money should first be spent to improve the basic science and technology rather than embarking on trials that probably will not be very useful.

Dr. David Williams, a professor at Indiana University who is working on gene therapy for several rare diseases, said the N.I.H. seems more willing to finance some clinical trials. But Dr. Williams's first clinical trial will be for cancer, because the National Cancer Institute has been more amenable to such trials than other institutes.

Some scientists say that even if the technology does not work yet, clinical trials could speed development. ''If I had a million dollars I couldn't suddenly treat 100 patients,'' said Dr. Chester B. Whitley of the University of Minnesota, who wants to do gene therapy for Hunter's syndrome. ''But I could treat one patient and learn from that and then treat three patients.''

Even if Government funding were available, it would probably go only through the initial safety testing, at a cost of about $200,000 to $600,000, researchers said. It would probably be up to companies to do the more expensive later-stage trials.

Most companies, particularly the new ones that are doing most of the gene therapy work, say they cannot afford to spend money on treatments for rare diseases because of the limited potential for payback.

''The commercial value of a product in that area is going to be less,'' said Dr. Stephen A. Sherwin, chief executive of Cell Genesys of Foster City, Calif. ''In a business setting, you have to consider that.'' His company is conducting seven gene therapy trials -- five for cancer and two for AIDS.

Cancer is also being emphasized because risky treatments traditionally are tested on terminal illnesses, Dr. Sherwin said. In addition, the technical problems that have stymied the use of gene therapy in inherited diseases may pose less of an obstacle in cancer or cardiovascular disease, other scientists said.

The problem with gene therapy so far is that researchers have not been able to deliver the genes in large enough quantities to the proper cells, or to have the genes ''expressed,'' or activated to produce the required protein for a sufficient length of time.

But for cancer, the genes usually would not need to be activated forever. One approach, for example, calls for injecting genes that cause the tumor cells to produce a protein that stimulates the body's own immune system, which then would attack the tumor. In clinical trials sponsored by Vical, a San Diego company, such an approach reduced the tumors by at least half in 17 percent of melanoma patients who had failed other therapies.

''For certain cancers and cardiovascular diseases, you don't need expression forever,'' said Dr. Ronald Crystal, professor of medicine at New York Hospital-Cornell Medical Center. Dr. Crystal is continuing work on hereditary diseases at his laboratory. But a company he co-founded, Genvec, is concentrating on gene therapy for cardiovascular disease, using genes for a protein to help grow new blood vessels in tissues with inadequate blood flow.

Some experts say that the search for cancer treatments has increased spending on gene therapy technology, which will eventually help people with genetic diseases.

''Maybe the quickest route to solving cystic fibrosis is to take a detour,'' said Dr. Alan E. Smith, chief scientific officer at Genzyme Corporation, a biotechnology company that conducted eight unsuccessful gene therapy trials for cystic fibrosis. Now the company is concentrating on cancer and cardiovascular disease as well as Gaucher's disease, a rare inherited disorder.

Mrs. Cohen is also hopeful that techniques developed for cancer gene therapy will be applied to her son's disease.

Other treatments for genetic disorders are being tried. Genzyme is treating Gaucher's using genetic engineering. The necessary gene is implanted in vats of cells, producing an enzyme that is sold to patients for about $150,000 a year.

In the ideal case, gene therapy would require a single injection of genes that would then allow the patient to make his or her own enzyme. But for a drug company, a one-time cure for a rare disease might offer less chance of profit.

The biggest problem with gene therapy has been developing the vectors -- usually partially disabled viruses -- that can deliver the genes to the cells. But scientists say progress has been made, and other techniques have been developed to do away with viruses altogether.

''It's going to work in the next couple of years for many more genetic diseases,'' said Dr. R. Michael Blaese, a gene therapy pioneer at N.I.H. who recently became chief scientific officer at Kimeragen, a new company. Rather than inject entire genes, the company's technology will just ''correct the typos'' in the patient's own genes. Dr. Blaese said the company's first clinical trial will probably be for a rare inherited liver disorder called Crigler-Najjar disease.

Avigen, a gene therapy company in Alameda, Calif., has improved the condition of dogs with hemophilia B for 20 weeks with a single injection of the gene for Factor IX, the missing blood clotting agent. The company, which hopes to begin human trials this year, uses a vector made from an adeno-associated virus, a type of virus that has received little attention.

Avigen's president, John Monahan, said the company would focus on more common inherited diseases rather than cancer. ''For cancer,'' he said, ''there's not even an agreement on what the gene should be.''